Sepsis continues to be the major cause of death in critically ill patients and often results in multiple organ failure. Sepsis-associated myocardial dysfunction is often profound and can lead to refractory hypotension and cardiovascular collapse.
Altered mitochondrial function and impaired oxidative phosphorylation have been implicated in the development of sepsis-induced cardiac dysfunction and dysfunction in other organs Diminished function of any of the electron transport complexes could limit aerobic ATP synthesis and lead to bioenergetic failure. Cytochrome oxidase (CcOX), the terminal oxidase of the respiratory chain, uses electrons donated by cytochrome c to reduce oxygen to water. Coupled with the reduction of oxygen, CcOX pumps hydrogen ions across the mitochondrial inner membrane to the inter-membrane space. This creates and maintains a hydrogen ion gradient between the inside of the mitochondria and the inter-membrane space. This gradient generates the proton motive force that is crucial for ATP synthesis.
Myocardial CcOX is inhibited during sepsis. This inhibition is competitive and reversible early following cecal ligation and puncture (CLP, a well-established, well-accepted animal sepsis model that closely mimics human sepsis) and progresses becoming noncompetitive and irreversible during the late phase of sepsis. The onset of the hypodynamic phase and mortality in sepsis coincide with maximal competitive CcOX inhibition.
Accordingly, a need exists for improved methods and compositions for treating CcOX mediated diseases or medical conditions.